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Because this noradrenergic (alpha-adrenergic) activation usually induces insomnia, the treatment was not administered in afternoon hours. When this side effect was observed, a small dose of 5-hydroxytryptophan (25 mg) was administered before supper, in order to counterbalance excessive hyper-noradrenergic induced activity. Five-hydroxytryptophan, a serotonin precursor, can be added to a small dose (15 mg) of mirtazapine (Remeron), administered before bed. This drug stimulates the release from central neuronal circuits of NA and 5HT, neurotransmitters both needed to facilitate a normal slow wave sleep (SWS). All benzodiazepines and/or gaba-mimetic drugs were banned because they provoke strong suppression of noradrenaline + dopamine (DA) + serotonin release (Lechin, van der Dijs et al., 1994). 

Considering that late-onset MG and thymoma patients show antibodies to striated muscle antigens (Aarli, 1999), a condition frequently leading to muscular atrophy, we administered growth hormone (4 IU weekly) to some of these patients in order to provoke muscle fiber regeneration (Daugaard, Laustsenet al., 1998). This additional therapeutic tool proved be highly effective in two cases.

Taking into account that f-5HT blocks the fetal more potently than the adult muscle acetylcholine receptor (Grassi, 1999), we administered small doses of tianeptine (a serotonin enhancer of platelet uptake - 6.75 mg each other day) (Lechin, van der Dijs et al., 1998b; 1998c).

Analytical Methods

Platelet aggregation was determined at 0 min and 5 min only, employing the adenosine diphosphate method described by Born (1962).

Results

Assessment of the therapeutic effects resulting from our neuropharmacological approach should properly be based on clinical, EMG and immunological parameters. However, we will also comment on some neurochemical and neuroautonomic induced effects (see Tables I to V).

Clinical Findings:

All MG patients showed a highly significant and sustained reduction of symptoms during acute (£ 6 days) and late (weeks and months) periods after starting the neuropharmacological therapy. Patients registered no relapses, no MG crises, nor new plasmapheresis after initiation of our treatment. Immunosuppressant drugs were totally eliminated. Suppression of steroids was acomplished progressively. Mestinon was also progressively omitted attaining until reaching complete or highly significant reduction. The total suppression of Mestinon was effected in all non-thymectomized patients and in three thymectomized cases. In the other thymectomized patients, Mestinon was reduced to a minimum.

Immunological Findings

Increased CD5+B self-reactive and CD8 (suppressor) lymphocytes were registered in all patients. They also showed immunological abnormalities consistent with the Th-2 profile (increased NK-cells, decreased NK-cell cytotoxicity, increased IgG and/or IgM plasma levels), increased CD45RO (memory T cells). These immunological abnormalities disappeared in all non-thymectomized patients after sustained neuropharmacological treatment (± 3 months). Thymectomized patients and some who had received prolonged immunotherapy presented an atypical profile of the immune disorder (see Tables IV and V). Most such abnormalities did not disappear despite the significant and sustained clinical improvement shown by these patients. Moreover, the thymectomized and immunosuppressed patients registered a lower recovery than that shown by the non-thymectomized or non-immunosuppressed patients.

Twenty-four out of the 27 non-thymectomized patients showed increased levels of ACh-receptor autoantibodies before neuropharmaco-logical treatment. After therapy, 20 of those 24 patients showed normalization or a great reduction of this parameter. On the other hand, an erratic response was observed in MG patients previously submitted to surgical or drug-induced immunosuppression.

Seven out of the 25 thymectomized patients showed Scl-70 auto-antibodies [usually registered in systemic lupus erythematous (SLE) patients]. Only one patient showed increased anti-striated muscle autoantibodies plus increased levels of ACh-R autoantibodies, before and after therapy. He was a 38-year-old male whose myasthenia gravis symptoms began in 1985. He was affected by hepatitis during childhood. He was rated as a II-a MG patient. The electromyography test was positive for MG. Thymectomized on Sept. 20, 1993, he was prescribed Mestinon therapy which he took for six years. He accepted neither steroids nor immunosuppressant drugs. We performed immunological investigations on March 3/99, May 18/99, and June 22/99 with similar immune abnormalities (reduced CD4/CD8 ratio plus increased T virgin cells). These abnormalities were found on all three occasions. Neither immunological nor serological abnormalities disappeared despite his clinical improvement with neuropharmaco-logical therapy.

Neuropharmacological, neurochemical and autonomic test results were normalized in all patients after completing our therapy. These tests paralleled clinical improvement.

Neurochemical Findings

. Noradrenaline but not adrenaline increased during these tests. The abnormal diastolic blood pressure (DBP) and heart rate (HR) responses returned to normal after one month of neuropharmacological therapy. Normalization of these autonomic parameters depends on the disappearance of adrenal gland hyperresponsiveness + recovery of central sympathetic (neural) activity

Discussion

Our results showed that although the onset of clinical improvement occurred rapidly (< one week), immunological normalization took months (2-3 months). When this stage of late improvement was obtained, doses of drugs were reduced. With regard to this, we observed that MG patients taking high Mestinon doses responded slowly to our neuropharmacological therapy. This finding may be associated with the fact that acetylcholinesterase inhibitors provoke down-regulation of ACh-receptors . We also found that MG patients taking Mestinon at night responded more slowly than those taking only diurnal Mestinon. We inferred that these patients do not sleep well because of a lack of muscular relaxation induced by the sustained enhanced neuromuscular nocturnal ACh-activity. This factor would contribute to aggravating the diurnal muscular fatigue they usually presented. Furthermore, considering that normalization of immunity as well as central noradrenergic activity occurs during sleep, mainly during phases III and IV of slow wave sleep (SWS) when growth hormone secretion peaks, it becomes clear why normalization of the sleep pattern is necessary to the recovery of all autoimmune diseases (Kelley, 1989).